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Crystals
Special Issues
X-ray Crystallography and Drug Discovery
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X-ray Crystallography and Drug Discovery

A special issue of Crystals (ISSN 2073-4352). This special issue belongs to the section "Biomolecular Crystals".

Deadline for manuscript submissions: closed (20 June 2024) | Viewed by 5686

Special Issue Editor

Dr. Lidia Ciccone

E-Mail Website
Guest Editor
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: amyloid proteins; medicinal chemistry; degenerative diseases; drug design; X-ray crystallography; chemical synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

High-resolution protein structures obtained by X-ray crystallography are a powerful tool in the drug discovery process. The atomic information about the target protein structure or the knowledge of the interaction of protein–ligand complexes contributes to driving the design of a new drug. Hence, structure-based drug discovery (SBDD) requires the use of structural information in drug development. In order to achieve this goal is essential to make high-ordered crystals keeping their quality unaltered from crystallization to data acquisition. Crystallization tips such as co-crystallization induced by streak seeding, microseeding, macroseeding, etc. can help to attain suitable reproducibility of crystals that diffract at high resolution.

Finally, in the drug discovery process, the synergy between the X-ray crystallography scientists and the medicinal chemistry and computational chemistry researchers is necessary to merge all information acquired for proposing new (or optimized) ligands as drug candidate molecules.

Dr. Lidia Ciccone
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Crystals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2100 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • target protein crystal structure
  • ligand-protein crystal complex
  • structure-based drug discovery
  • co-crystallization
  • ligand soaking
  • protein-ligand co-expression
  • Cryoprotection
  • virtual screening
  • molecular docking
  • ligand chemical synthesis
  • natural compounds
  • X-ray source
  • leads identification

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Published Papers (3 papers)

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Research

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10 pages, 3607 KiB  
Article
High Resolution Crystal Structure of the Pyruvate Kinase Tetramer in Complex with the Allosteric Activator Mitapivat/AG-348
by Xiao Han, Tatyana Sandalova, Cheng Zhang, Adil Mardinoglu, Adnane Achour and Renhua Sun
Crystals 2024, 14(5), 441; https://doi.org/10.3390/cryst14050441 - 5 May 2024
Viewed by 1736
Abstract
Pyruvate kinase (PK) deficiency is a rare genetic disorder that affects this critical enzyme within the glycolysis pathway. In recent years, Mitapivat (MTPV, AG-348) has emerged as a notable allosteric activator for treating PK deficiency. However, the allosteric regulatory effects exerted on PK [...] Read more.
Pyruvate kinase (PK) deficiency is a rare genetic disorder that affects this critical enzyme within the glycolysis pathway. In recent years, Mitapivat (MTPV, AG-348) has emerged as a notable allosteric activator for treating PK deficiency. However, the allosteric regulatory effects exerted on PK by MTPV are yet to be comprehensively elucidated. To shed light on the molecular mechanisms of the allosteric effects, we employed crystallography and biophysical methods. Our efforts yielded a high-resolution crystal structure of the PK tetramer complexed with MTPV at 2.1 Å resolution. Isothermal titration calorimetry measurements revealed that MTPV binds to human PK with an affinity of 1 μM. The enhanced structural details now allow for unambiguous analysis of the MTPV-filled cavity intricately embedded within the enzyme. Finally, the structure suggests that MTPV binding induces an allosteric effect on the B-domain situated proximal to the active site. In summary, our study provides valuable insights into the allosteric regulation of PK by MTPV and paves the way for further structure-based drug optimization for therapeutic interventions in PK deficiency. Full article
(This article belongs to the Special Issue X-ray Crystallography and Drug Discovery)
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13 pages, 3227 KiB  
Article
A Tetranuclear Ni(II)-Cubane Cluster Molecule Build by Four µ3-O-Methanolate (MeO) Ligands, Externally Cohesive by Four Unprecedented Bridging µ2-N7,O6-Acyclovirate (acv-H) Anions
by Jeannette Carolina Belmont-Sánchez, Duane Choquesillo-Lazarte, Ricardo Navarrete-Casas, Antonio Frontera, Alfonso Castiñeiras, Juan Niclós-Gutiérrez and Antonio Matilla-Hernández
Crystals 2023, 13(1), 7; https://doi.org/10.3390/cryst13010007 - 21 Dec 2022
Cited by 1 | Viewed by 1933
Abstract
Metal ion interactions with nuclei acids and their constituents represent a multi-faceted and growing research field. This contribution deals with molecular recognition between synthetic purine 17 nucleosides and first-row transition metal complexes, with O- and/or N-amino chelators which are able to 18 engage [...] Read more.
Metal ion interactions with nuclei acids and their constituents represent a multi-faceted and growing research field. This contribution deals with molecular recognition between synthetic purine 17 nucleosides and first-row transition metal complexes, with O- and/or N-amino chelators which are able to 18 engage in intra-molecular N-H···(N or O) and O-H···(N or O) interligand interactions. Crystals of these complexes can also display inter-molecular aromatic π-stacking and/or other non-conventional interactions. In this manuscript, we used 2-(2-aminoethoxy)ethanol (2aee) as a potential N,O(e),O(ol)-chelator for nickel(II). However, unexpectedly, the reaction between NiCl2, acyclovir (acv), and 2aee in methanol afforded parallelepiped apple-green crystals of [Ni(acv-H)(MeO)(H2O)]4·8H2O, (1) a tetranuclear molecule with an equimolar Ni(II):µ3-methanolate(1-):µ2-N7,O6-acyclovirate(1-) (acv-H) ratio. The µ2-N7,O6-(acv-H) metal-binding pattern (MBP) is unprecedented in terms of both its anionic and bridging roles. The single-crystal X-ray diffraction structure as well as thermogravimetric analysis and the (FT-IR +Vis-UV) spectra of 1 are reported. Theoretical density functional theory (DFT) calculations are used to analyse the antiparallel π-stacking interactions that govern the formation of self-assembled dimers in the solid state. Full article
(This article belongs to the Special Issue X-ray Crystallography and Drug Discovery)
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Review

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14 pages, 2672 KiB  
Review
Fragment Screening in the Development of a Novel Anti-Malarial
by Xiaochen Du, Ran Zhang and Matthew R. Groves
Crystals 2023, 13(12), 1610; https://doi.org/10.3390/cryst13121610 - 21 Nov 2023
Cited by 1 | Viewed by 1297
Abstract
Fragment-based approaches offer rapid screening of chemical space and have become a mainstay in drug discovery. This manuscript provides a recent example that highlights the initial and intermediate stages involved in the fragment-based discovery of an allosteric inhibitor of the malarial aspartate transcarbamoylase [...] Read more.
Fragment-based approaches offer rapid screening of chemical space and have become a mainstay in drug discovery. This manuscript provides a recent example that highlights the initial and intermediate stages involved in the fragment-based discovery of an allosteric inhibitor of the malarial aspartate transcarbamoylase (ATCase), subsequently shown to be a potential novel anti-malarial. The initial availability of high-resolution diffracting crystals allowed the collection of a number of protein fragment complexes, which were then assessed for inhibitory activity in an in vitro assay, and binding was assessed using biophysical techniques. Elaboration of these compounds in cycles of structure-based drug design improved activity and selectivity between the malarial and human ATCases. A key element in this process was the use of multicomponent reaction chemistry as a multicomponent compatible fragment library, which allowed the rapid generation of elaborated compounds, the rapid construction of a large (70 member) chemical library, and thereby efficient exploration of chemical space around the fragment hits. This review article details the steps along the pathway of the development of this library, highlighting potential limitations of the approach and serving as an example of the power of combining multicomponent reaction chemistry with fragment-based approaches. Full article
(This article belongs to the Special Issue X-ray Crystallography and Drug Discovery)
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